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Exploiting the proteome to improve the genome-wide genetic analysis of epistasis in common human diseases

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Abstract

One of the central goals of human genetics is the identification of loci with alleles or genotypes that confer increased susceptibility. The availability of dense maps of single-nucleotide polymorphisms (SNPs) along with high-throughput genotyping technologies has set the stage for routine genome-wide association studies that are expected to significantly improve our ability to identify susceptibility loci. Before this promise can be realized, there are some significant challenges that need to be addressed. We address here the challenge of detecting epistasis or gene–gene interactions in genome-wide association studies. Discovering epistatic interactions in high dimensional datasets remains a challenge due to the computational complexity resulting from the analysis of all possible combinations of SNPs. One potential way to overcome the computational burden of a genome-wide epistasis analysis would be to devise a logical way to prioritize the many SNPs in a dataset so that the data may be analyzed more efficiently and yet still retain important biological information. One of the strongest demonstrations of the functional relationship between genes is protein-protein interaction. Thus, it is plausible that the expert knowledge extracted from protein interaction databases may allow for a more efficient analysis of genome-wide studies as well as facilitate the biological interpretation of the data. In this review we will discuss the challenges of detecting epistasis in genome-wide genetic studies and the means by which we propose to apply expert knowledge extracted from protein interaction databases to facilitate this process. We explore some of the fundamentals of protein interactions and the databases that are publicly available.

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Acknowledgments

This publication was funded in part by National Institute of Health grants LM009012 and AI59694. We would like to thank Drs. Scott Gerber, David Jewell, Dean Madden and Mike Whitfield for helpful discussions that lead to some of the ideas in this paper.

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Authors and Affiliations

  1. Computational Genetics Laboratory, Norris-Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH, USA

    Kristine A. Pattin

  2. Department of Genetics, Norris-Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH, USA

    Jason H. Moore

  3. Department of Community and Family Medicine, Norris-Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH, USA

    Jason H. Moore

  4. Department of Computer Science, University of New Hampshire, Durham, NH, USA

    Jason H. Moore

  5. Department of Computer Science, University of Vermont, Burlington, VT, USA

    Jason H. Moore

  6. Translational Genomics Research Institute, Phoenix, AZ, USA

    Jason H. Moore

  7. Dartmouth-Hitchcock Medical Center, 706 Rubin Building, HB 7937, One Medical Center Drive, Lebanon, NH, 03756, USA

    Jason H. Moore

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  1. Kristine A. Pattin
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Correspondence to Jason H. Moore.

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Pattin, K.A., Moore, J.H. Exploiting the proteome to improve the genome-wide genetic analysis of epistasis in common human diseases. Hum Genet 124, 19–29 (2008). https://doi.org/10.1007/s00439-008-0522-8

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  • DOI: https://doi.org/10.1007/s00439-008-0522-8

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